ABSTRACT Alzheimer's disease (AD) is the most common cause of age-related dementia characterized by memory loss and cognitive decline. One of the pathological hallmarks of AD at the molecular level is the presence of neurofibrillary tangles composed of aggregates of hyperphosphorylated tau in the neurons leading to severe proteotoxic stress in these cells. Sustained proteotoxic stress typically results in neuronal cell death culminating in brain atrophy, a prominent pathological feature of AD. Given that tau can be degraded by the proteasome as well as the autophagy-lysosomal network, possible defects in one or both of these catabolic pathways could explain its accumulation in the diseased neurons. Consistent with this notion, accumulating evidence points to a progressive decline in the function of both the proteasome and the autophagy-lysosomal network during the aging process. Therefore, it is important to understand how these protein clearance systems operate in cells of neuronal origin and elucidate how these cells handle proteotoxic stress. Our previous studies have established the transcription factor Nrf1as a key player in responding to cellular proteotoxic stress. Nrf1, by its ability to induce de novo synthesis of proteasome subunit genes in response to proteasome inhibitors, promotes the recovery of proteasome activity, thus mitigating proteotoxic stress and enhancing cellular survival. Interestingly, our preliminary data indicate that under similar circumstances, Nrf1 can also transcriptionally upregulate multiple components of the autophagy pathway, and thus could offer the cells an additional route to cope with proteotoxic stress. Here we propose to investigate this phenomenon further in cells of neuronal origin that are relevant to AD. If successful, our studies could cement the role of Nrf1 as a master transcription factor that controls the two major arms of the cellular protein quality control pathways ? the ubiquitin-proteasome system, and autophagy in neuronal cells. This could lead to future studies aimed at the development of novel strategies to enhance these protein degradation pathways to mediate tau clearance and alleviate proteotoxic stress in the AD neurons.